Analeptic compositions and method



body. The compounds are analeptics.

United States Patent 3,301,758 ANALEPTIC COMPOSITIONS AND METHOD Carl D. Lunsford, Richmond, and Albert D. Cale, Jr.,

Bon Air, Va., assignors to A. H. Robins Company, Incorporated, Richmond, Va., a corporation of Virginia No Drawing. Filed May 26, 1965, Ser. No. 459,087 37 Claims. (Cl. 16765) The present application is a continuation-in-part of our prior-filed copending application Serial No. 237,286, filed November 13, 1962, now U.S. Patent 3,192,210, issued June 29, 19-65, in which a requirement for restriction is of record, which application is in turn a division of Serial No. 156,945, filed December 4, 1961, now U.S. Patent No. 3,192,221, itself a continuation-in-part of Serial No. 88,036, filed February 9, 1961, now U.S. Patent No. 3,192,230. The present invention relates to certain heterocyclic organic compounds which may be referred to as 4-(omega-substituted,alkyl)-2-pyrrolidinones and 4-(omega substituted ,alkyl)-2-thionpyrro1idinones and is more particularly concerned with compositions of 4- (omega-substituted alkyl)-3,3-disubstituted-l-substituted- 2-pyrrolidinones and 4-(omega-substituted alkyl)3,3-disubstitlted-1-substituted-2-thionpyrrolidines .and a method of treating therewith. The invention is especially concerned with such compositions and method which embody or employ a compound of the formula:

A RI! R! wherein: A is lower-alkyl, cycloalkyl, monocarbocyclic aryl, or monocarbocyclic aralkyl; R is lower-alkyl, loweralkenyl, cycloalkyl, monocarbo-cyclic aryl, monocarbocyclic aralkyl, pyridyl, thienyl, or thenyl; R'- is loweralkyl lower-alkenyl, cycloalkyl, cycloalkenyl, monocarbocyclic aryl, or m-onocarbocyclic aralkyl; R" is hydrogen or methyl, [a maximum of one R" being other than hydrogen; n is zero or one; Z is cyano, carb-lower-alkoxy, carbonyl halide, lower-alk-anoyl, and aminocarbonyl; and

- E is oxygen or sulfur.

The compounds of the invention having the foregoing formula are generally characterized by important pharmacological activity, indicative of their use in counteracting certainphysiological abnormalities in an animal Certain compounds of the series are extremely potent and long acting .analeptics, stimulating respiration and antagonizing central nervous system depression and exhibiting a particularly durable antagonism against barbiturate-induced depression or poisoning at dose levels considerably below that at which untoward side effects appear. The cyano compounds, for. example, and other potent compounds set forth in Table I, are especially potent analeptics. The compounds which are strong analeptics are generally also hypertensives.

It is accordingly an object of this invention to provide novel and useful compositions embodying certain 4- (omega-substituted -alkyl)-2-pyrrolidinones and -2-thionpyrrolidinones as active ingredient and a method for the treatment of a living animal body therewith. Other objects of the invention will be apparent to one skilled in methyl-3-heptenyl.

the art, and still other objects will become apparent hereinafter.

In the definitions of symbols in the foregoing formula and where they appear elsewhere throughout this specification, the terms have the following significance.

By monocarbocyclic aryl radical is menat an aryl radical of the benzene series, having six ring carbon atoms, and this term includes the unsubstituted phenyl radical and phenyl radicals substituted by any radical or radicals which are not reactive or otherwise interferring under conditions of the reaction, such as n-itro, loweralkoxy, lower alkylmercapto, lower-alkyl, halo, and the like. The substituted-phenyl radicals have preferably no more than one to three substituents such as those given .above and, furthermore, these substituents can be in various available positions of the phenyl nucleus and, where more than one substituent is present, can be the same or different and can be in various posit-ion combinations relative to each other. The lower-alkyl, loweralkoxy, and lower-alkylmercapto substituents each have preferably from one to three carbon atoms which can be arranged as straight or branched chains. A total of fifteen carbon atoms in the monocarbocyclic aryl radical is the preferred maximum.

In the foregoing definition of R, certain cyclic radicals are referred to. When pyridyl is referred to, e.g., the 3- or 4-pyridyl radicals are included. When thienyl or thenyl radicals are referred to, these may be, for example, the S-thienyl or 2- or 3-thenyl radicals.

The term lower-alkyl as used herein includes straight and branched chain radicals of up to eight carbon atoms inclusive and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl, octyl, and the like. The term alkenyl includes straight .and branched chain radicals of two up to eight carbon atoms inclusive and includes such groups as vinyl, allyl, methallyl, 4-pentenyl, 3-hexenyl, and 3- The term cycloalkyl as used herein includes primarily cyclic alkyl radicals containing three up to nine carbon atoms inclusive and encompasses such groups as cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, methylcyclohexyl, propylcyclohexyl, ethylcyclopentyl, propylcyclopentyl, dimethylcyclohexyl, cycloheptyl, and cyclooctyl. The term cycloalkenyl as used herein includes cyclic alkenyl radicals containing up to nine carbon atoms inclusive and encompasses such usual radicals as 1- and Z-cyclohexenyl and 1- and 2-cyclopentenyl. Included in the term aralkyl are lower-alkyl substituted mono-carbocyclic aryl groups such as benzyl, phenethyl, methylbenzyl, phenpropyl and the like. The radicals R and R in the above formula, as stated in the foregoing, are inclusive of such groups as lower-alkyl, cycloalkyl, and aralkyl, and are preferably although not necessarily radicals of a solely hydrocarbon nature.

When halogen is referred to herein, preferably but not necessarily a halogen of atomic weight in excess of 19 is employed. Of the halogens, chlorine is preferred.

By aminocarbonyl, as used herein, is meant an aminocarbonyl radical wherein amino is selected from the group consisting of primary amino, N-(lower-alkyl)amino, N,N-di-(lower-alkyl)amino, N,N di (monocyclic alkyl) amino wherein each monocyclic alkyl has up to a maximum of nine carbon atoms, and saturated heterocyclic amino radicals having less than 12 carbon atoms and having up to a maximum of two hetero atoms. in the heterocyclic ring. The term aminocarbonyl thus encompasses not only the primary amino containing aminocarbonyl (carbamido) radicals, but also the corresponding N-phenylor N-(lower-alkyl)-carbamido and N,N-di- (lower-alkyl)-carbamido radicals as well as the corresponding -N,N-monocyclic alkyl or saturated heterocyclic carbamido radicals, wherein the saturated monocyclic heterocyclic radical is variable in accord with the following.

Among the suitable amino groups which may be present in the carbamido radical are primary, secondary and tertiary amino radicals, such as unsubstituted amino (NH (lower-alkyl -amino; dilower-alkyl) -amino (lower-alkenyl)-amino; di-(lower-alkenyl)amino; phenylamino; (hydroxy-lower-alkyl)-amino; di-(hydroxy-loweralkyl)-amino; basic saturated monocyclic heterocyclic radicals of less than twelve carbon atoms, as exemplified by piperidino; (lower-alkyl)-piperidino, e.g., 2-, 3,- or 4- (lower-alkyl) piperidino; dilower-alkyl piperidino, e.g., 2,4-, 2,6-, or 3,5-di-(lower-alkyl)piperidino; (lower-alkoxy)-piperidino; pyrrolidino; (lower-alkyl)-pyrrolidino; di-(lower-alkyl) -pyrrolidino; (lower-alkoxy) -pyrrolidino; morpholino; (lower-alkyl)-morpholino; di-(lower-alkyl)- morpholino; (loWer-alkoxy)-morpholino; thiomorpholino; (lower-alkyl) -thiomorpholino; di- (lower-alkyl -thiomorpholino; (lower alkoxy) thiomorpholino; piperazino; (lower-alkyD-piperazino (e.g., C- or N -methylpiperazino), di-C-(lower-alkyl) -piperazino; N -(lower-alkyl)-C- (lower-alkyl)-piperazino; N-(hydroxy-lower alkyl)-piperazino; N-(lower-aliphatic acyloxy lower-alkyD-piperazino [e.g., N-acetoxy-, isobu-tyroxy-, or octanoyloxyethyl or propyl piperazino]; lower alkoxy) piperazino; and (loWer-carb alkoxy) -piperazino.

The present invention provides valuable pharmaceutical compositions of pharmacologically-active organic compounds, having an omega-substituted alkyl substituent in the four position, and a method of treating therewith. Although pyrrolidinones having substituents on the l-nitrogen atom are known, to the best of our knowledge no compounds of the present type, having a substituted alkyl group attached to the 4-position of the 2-pyrrolidinone or 2-thionpyrrolidinone ring, substitution in the 1-position, and disubstitution in the 3position of said ring, have heretofore been known or preparable by any method, neither have the starting materials therefore been known heretofore. The preferred compounds for all purposes are the 3,3-diaryl compounds, especially the 1-loWer-alkyl-3,3-diphenyl compounds.

The compounds which are utilized as active ingredient in the compositions and method of the invention are described and claimed per se in parent application Serial No. 237,286, now US Patent 3,192,210, and are prepared as disclosed therein. The disclosure of the said US. Patent 3,192,210 is hereby incorporated into this application in toto by reference and by reference made a part thereof. Of the compounds, falling within the scope of the foregoing broad formula, disclosed in the said US. patent, the following type compounds and species deserve special attention:

4-(fl-cyanoethyl)-3,3-diphenyl-1-lower-alkyl-2-pyrrolidinone 4-( B-cyanoethyl)-3,3-diphenyl-1-isopropyl-2-pyrro1idinone 4-('y-cyanopropyl)-3,3-diphenyl-1-lower-alkyl-Z-pyrrolidinone 1-lower-alkyl-3,3 -diphenyl-2-pyrrolidinone-4-propionarnide 1-loWer-alkyl-3,3-diphenyl-2-pyrrolidinone-4- (N-loweralkylpropionamide) 1-isopropyl-3,3-diphenyl-2-pyrrolidinone-4-(N-methylpropionamide) 1-lower-alkyl-3,3-diphenyl-2-pyrrolidinone-4-(N,N-dilower-alkylpropionamide) 1-isopropyl-3,3-diphenyl-2-pyrrolidinone-4- (N,N-dimethylpropionamide) 1-lower-alkyl-3,3 -diphenyl-4- li-lower-alkanoylethyl) -2- pyrrolidinone 1-isopropyl-3,3 -diphenyl-4- fi-propionylethyl -2-pyrrolidinone 1-lower-alkyl-3,3-diphenyl-2-pyrro1idinone-4-propionyl chloride Lower-alkyl 1-lower-alkyl-3,3-diphenyl-2-pyrrolidinone-4- propionate 1-lower-alkyl-3 ,3-diphenyl-4- [,B-lower-alkyleneiminocarbonylethyl] -2-pyrrolidinone 1-isopropyl-3,3-diphenyl-4- B-pyrrolidinocarbonylethyl] 2-pyrrolidinone 4- -cyanoisopropyl) -3 ,3-diphenyl-1-lower-alkyl-2-pyrr0lidinone 4- ('y-cyano-fl-propyl -3 ,3 -diphenyl-1-ethyl-2-pyrrolidinone 4- fi-morpholinocarbonylethyl -3,3-dipheny1- 1 -isopropyl- 2-pyrrolidinone 4- fi-cyanoethyl) -3,3-diphenyl-l-lower-alkyl-Z-pyrrolidinonethion 4- B-cyanoethyl) -3,3-diphenyl- 1 -isopropy l-2-thioripyrrolidinone 1-1ower-alkyl3, 3 -diphenyl-2-pyrrolidinonethion-4- (N,N-

di-lower-alkylpropionamide) 1-isopropyl-3 3 -diphenyl-2-thionpyrrolidinone-4-dimetl1ylpro pionamide 1-lower-alkyl-3 3 -diphenyl-2-pyrrolidinonethion-4-propionyl chloride 1-isopropyl-3,3-diphenyl-Z-thionpyrrolidinone-4-propionyl chloride Lower-a1kyl-3 3 -diphenyl-1-lower-alkyl-2-pyrrolidinonethion-4-propionate Ethyl-3,3-diphenyl-1-isopropyl-Z-thionpyrrolidinone-4- propionate FORMULATION AND ADMINISTRATION Effective quantities of any of the foregoing pharmacologically active compounds may be administered to a living animal body in any one of various ways, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. The 1-lower-alkyl-3,3-disubstituted-4-(omega cyanoalkyl)-2- pyrrolidinones and 2-thionpyrrolidinones, as Well as the other very potent compounds set forth in Table I, represent a preferred group of highly active compounds, of which the l-ethyl and l-isopropyl compounds are outstandingly active. Preferred groups at the 3-position are phenyl radicals as the 3,3-diphenyl compounds are like- Wise outstanding in their activity.

Although very small quantities of the active materials of the present invention are effective when minor therapy is involved or in cases of administration to subjects having a relatively low body weight, unit dosages are usually five milligrams or above and preferably twenty-five, fifty or one hundred milligrams or even higher, depending of course upon the emergency of the situation and the particular result desired. Five to fifty milligrams appears optimum per unit dose, while usual broader ranges appear to be one to milligrams per unit dose. The active agents of the invention may be combined with other pharmacologically active agents, or with buffers, antacids or the like, for administration and the proportion of the active agent in the compositions may be varied widely. It is only necessary that the active ingredient constitute an effective amount, i.e., such that a suitable effective dosage will be obtained consistent with the dosage form employed. Obviously, several unit dosage forms may be administered at about the same time. The exact individual dosages as well as daily dosages in a particular case will of course be determined according to established medical principles under the direction of a physician or veterinarian. Results upon administration of these novel materials have thus far proved extremely gratifying.

The following formulations are representative for all of the pharmacologically active compounds of the invention, but have been especially designed to embody as active ingredient the 1-lower-alkyl-3,3-diphenyl(omegacyanoethyl)-2-pyrrolidinones and 2-thionpyrrolidinones, especially the l-ethyl and l-isopropyl compounds, and in particular AHR Compounds 677, 681, 697, 709 and 698 and compounds of the subgeneric class of which these specific compounds are representative.

FORMULATIONS (1) Capsules.--Capsules of 5 mg., 25 mg., and 50 mg. of active ingredient per capsule are prepared. With the higher amounts of active ingredient, reduction may be made in the amount of lactose.

' Per capsule Typical blend for encapsulation: mg.

Active ingredient, as salt 5.0 Lactose 296.7 Starch 129.0 Magnesium stearate 4.3

Total 435.0

Additional capsule formulations preferably contain a higher dosage of active ingredient and are as follows:

Ingredients 100 mg. per 250 mg. per 500 mg. per

Capsule Capsule Capsule Active Ingredient, as salt 100. 250.0 500. 0 Lactose 231. 126. 5 31. 1 Starch 99. 2 54. 2 13. 4 Magnesium stearate. 4. 3 4. 3 5. 5

Total 435. 0 435. 0 550. 0

In each case, uniformly blend the selected active ingredient with lactose, starch, and magnesium stearate and encapsulate the blend.

(2) Tablets.A typical formulation for a tablet containing 5.0 mg. of active ingredient per tablet follows. The formulation may be used for other strengths of active ingredient by adjustment of weight of dicalcium phosphate.

Per tablet (1) Active ingredient 5.0 (2) Corn starch 13.6 (3) Corn starch (paste) 3.4 (4) Lactose 79.2 5) Dicalcium phosphate 68.0 (6) Calcium stearate 0.9

Total 170.1

7 Uniformly blend 1, 2, 4 and 5. Prepare 3 as a 10 percent paste in water. Granulate the blend with starch paste and pass the wet mass through an eight mesh screen. The wet granulation is dried and sized through a twelve mesh screen. The dried granules are blended with the calcium stearate and compressed.

Additional tablet formulations preferably contain a higher dosage of the active ingredient and are as follows:

A. 50 mg. tablet Per tablet Ingredients: mg.

Active ingredient, as salt 50.0 Lactose 90.0 Milo starch 20.0 Corn starch 38.0 Calcium stearate 2.0

Total 200.0

Uniformly blend the active ingredient, lactose, milo starch, and corn starch. This blend is granulated using water as a granulating medium. The wet granules are passed through an eight mesh screen and dried at to degrees Fahrenheit overnight. The dried granules are passed through a number ten mesh screen and blended with the proper amount of calcium stearate and this blend is then converted into tablets on a suitable tablet press.

Uniformly blend the active ingredient, lactose, dicalcium phosphate, starch and milo starch. This blend is granulated with water and the Wet mass is passed through a number eight mesh screen. The Wet granules are dried at 140 160 degrees Fahrenheit overnight. The dried grantiles are passed through a number ten mesh screen. These dried granules are blended with the proper weight of calcium stearate and the lubricated granules are then converted into tablets on a suitable tablet press.

C. 250 mg. tablet Per tablet,

Ingredients: mg.

Active ingredient, as salt 250.0 Corn starch 56.0 Carbowax 6000 (polyethylene glycol of M.W.

approximately 6000) 25.0 Lactose 35.0 Magnesium stearate 4.0

Total 370.0

Uniformly blend the active ingredient, Carbowax 6000, lactose, and one-half the weight of magnesium stearate required. This blend is then slug-ged on a suitable tablet press. These slugs are granulated through a ten mesh screen on an oscillating granulator. These granules are then blended with the remainder of the magnesium stearate and the lubricated granules are then converted into tablets on a suitable tablet press.

D. 500 mg. tablet Per tablet, Ingredients: mg.

Active ingredient, as salt 500.0 Corn starch (wet) 86.4 Milo starch 32.4 Calcium stearate 3.2 Corn starch.(dry) 26.0

Total 648.0

Uniformly blend the active ingredient, corn starch and milo starch. This blend is wet granulated using water and the wet mass is passed through a number eight mesh screen. These wet granules are dried overnight at 140- 160 degrees Fahrenheit. The dried granules are passed through a number ten mesh screen. The dried granules and weighed amounts of corn starch and calcium stearate are uniformly blended and these lubricated granules are compressed on a suitable tablet press.

7 (3) Injectable2% sterile sluti0n.

Per cc. Active ingredient, mg. Preservative, e.g., chlorobutanol, percent weight/volume 0.5

Water for injection, q.s.

Prepare solution, clarify by filtration, fill into vials, seal, and autoclave.

(4) The pharmacologically active compounds provided by the present invention may also be administered successfully by embodying an effective quantity thereof in an injectable suspension for injection into an animal body, in oral powders, suspensions or syrups, and in other acceptable dosage forms.

Representative compositions of the present invention were tested against a known analeptic, nikethamide. As purchased on the open market, this compound was supplied as a 250 mg./ml. aqueous solution.

OBJECTIVE The purpose of these studies was to determine the relative activity of representative compounds in this series of compounds compared to nikethamide, a well known analeptic agent.

EXPERIMENTAL Method-Adult mongrel dogs (either sex) were used following an overnight fast. Surgical anesthesia was induced with intravenous phenobarbital sodium, 125 to 175 mg./kg. according to the requirement in each animal. The numbers of animals employed were: 1 to 5 with each AHR compound; and 5 with nikethamide. A Grass Model 5 Polygraph was used for recording blood pressure from a carotid artery (Statham P23AC transducer) and respiration from a tracheal cannula (Grass Model PTSA Volumetric Low Pressure Transducer). Changes in the level of anesthesia were deter-mined by gross observation of the animal and by application of stimuli appropriate for investigating the functional integrity of pain, blink and corneal reflexes.

Aqueous or propylene glycol solutions of experimental compounds were administered via a femoral vein. In most instances the initial dose was 1 tug/kg. and each subsequent dose was doubled at 1 0 to minute intervals until pharmacologic and/ or lethal effects were produced. If such doses proved to be too high (e.g., certain AHR compounds) or too low (e.g., nikethamide), the proper adjustment was made in subsequent experiments.

Results.-The results of this study are summarized in Table I. All AHR compounds were capable of markedly increasing the depth and frequency of breathing (respiration). In addition tothe respiratory effect, all AHR compounds were found to be potent antagonists of the central nervous system depressant properties of the anesthetic agent.

Both magnitude and duration of the stimulant effect on respiration of the anesthetized dog were increased as the dose of AHR compounds was increased. Indeed, it was frequently possible to stimulate respiration for several hours following a single injection. Analeptic effects such as restoration of the integrity of blink, corneal, and pain reflexes, increased skeletal muscular tone, and spontaneous body movements occurred consistently with the 1,3,3,4-tetra-substituted-2-pyrrolidinones.

In contrast to the 1,3,3,4-tetra-substituted-2-pyrrolidinones and thionpyrrolidinones, nikethamide was found to exert a weak and transient stimulant effect on respiration. Intravenous doses of to 80 mg./kg. were necessary to produce a modest effect on respiration. The respiratory effect of nikethamide was extremely brief in nature no matter what dose was used. Doses as high as 640 mg./ kg. failed to elicit and observable analeptic effects such as a restoration of blink, corneal, or pain reflexes. Spontaneous body movements were never observed followingtreatment with nikethamide.

TABLE I.COMPARATIVE ACTIVITY OF 1,3,3,4TETRA- SUBSTITUTED-2-PYRROLIDINONES AND TI-IIONPYR- ROLIDINONES WITH NIKETHAMIDE CaH5 -OH2CH2Z Minimum Effective IV Dose (mg/kg) with regard to AHR No. A R Z Respiratory Analeptic Stimula- Eflects 2 tion CeHs i-CaHv C 1 1 00115 i-C3H1 CONH2 4 8 C0115 PC3117 CON(OH3)2 1 1 CeHs i-CaH' CONHCHa 2 4 697 CsHs 1-CsH7 CON S 1 (C6) 1 1 739 OeHs 1-03H7 COC2H5. 2 4 709 oaHs l-CaH7 COOC2H5 1 l C ON S (C4) 1 1 1 2 CONHO4H 2 2 HzCN 2 4 C O 0 Q2115. 2 2 40-80 640 tharnide.

1 E=Oxygen (0) except compounds AHR-762 and AHR-781, where Efiects=one or more of the following: return of blink and/or corneal reflexes, increased skeletal muscular tone, body movements, ability to respond to auditory and/or visual stimuli.

Summary-The foregoing Table I shows clearly that all of the AHR compounds of this invention are far superior to nikethamide.

The activity of the active agents of the present invention, as evidenced by tests in lower animals, is indicative of utility based on their valuable activity in human beings as well as in lower animals. Clinical evaluation in hu man beings has not been completed, however. It will be clearly understood that the distribution and marketing of any compound or composition falling within the scope of the present invention for use in human beings will of course have to be predicated upon prior approval by governmental agencies, such as the US. Federal Food and Drug Administration, which are responsible for and authorized to pass judgment on such questions.

Various modifications and equivalents will be apparent to one skilled in the art and may be made in the compounds, compositions, and methods of the present invention without departing from the spirit or scope thereof, and it is therefore to be understood that the invention is to be limited only by the scope of the appended claims.

We claim:

1. A process which comprises administering to a living animal body, for its analeptic effect, an effective amount of a compound selected from the group consisting of 4 (omega substituted alkyl) 2 pyrrolidinones and 2- thionpyrrolidinones of the formula:

wherein Z is selected from the group consisting of cyano,

carb-l-ower-alkoxy, carbonyl halide, lower-alkanoyl, and aminocarbonyl wherein amino? is selected from the group consisting of primary amino, N-(lower-alkyl) amino, N,N-di-(lower-alkyl)amino, N,N-di-(monocyclic alkyl) amino wherein each monocyclic alkyl has up to a maximum of nine carbon atoms, and saturated heterocyclic amino radicals having less than 12 carbon atoms and having up to a maximum of two hetero atoms in the heterocyclic ring,

A is selected from the group consisting of loweralkyl, cycloalkyl having up to a maximum of nine carbon atoms, monocarbocyclic aryl, and monocarbocyclic aralkyl,

R is selected from the group consisting of lower-alkyl, lower-alkenyl, cycloalkyl having up to :a maximum of nine carbon atoms, monocarbocyclic aryl, monocarbocyclic aralkyl, pyridyl, thienyl, and thenyl,

R is selected from the group consisting of lower-alkyl, lower-alkenyl, cycloalkyl having up to a maximum of nine carbon atoms, cycloalkenyl having up to a maximum of nine carbon atoms, and monocarbocyclic aralkyl,

R" is selected from the group consisting of hydrogen and methyl, a maximum of one R being other than hydrogen,

wherein E is selected from the group consisting of oxygen and sulfur,

wherein monocarbocyclic aryl and monocarbocyclic aralkyl has at most fifteen carbon atoms and has a radical which is selected from the group consisting of phenyl, nitrophenyl, lower-alkoxyphenyl, loweralkylmercaptophenyl, lower-alkylphenyl, and halophenyl, and wherein alkyl in aralkyl is lower-alkyl, and wherein n is selected from zero and one.

2. A process according to claim 1, wherein the active ingredient is administered together with a pharmaceutically acceptable carrier therefor and in an amount of about one to 100 milligrams.

3. The process of claim 2 wherein the active compound is 4 (B cyanoethyl) 3,3 diphenyl 1 lower alkyl- 2-pyrrolidinone.

4. The process of claim 2 wherein the active compound is 4 (fi cyanoethyl) 3,3 diphenyl 1 isopropyl- 2-pyrrolidinone.

5. The process of claim 2 wherein the active compound is 4 ('y cyanopropyl) 3,3 diphenyl 1 lower alkyl- 2-pyrrolidinone.

6. The process of claim 2 wherein the active compound is 1 lower alkyl 3,3 diphenyl 2 pyrrolidinone- 4-propionamide.

7. The process of claim 2 wherein the active compound is l lower alkyl 3,3 diphenyl 2 pyrrolidinone 4- (N-lower-alkylpropionamide) 8. The process of claim 2 wherein the active compound is 1 lower alkyl 3,3 diphenyl 2 pyrrolidinone 4- (N,N-di-lower-alkylpropionamide 9. The process of claim 2 wherein the active compound is l-lower-alkyl 3,3 diphenyl-4-(fi-lower-alkanoylethyl)- 2-pyrrolidinone.

10. The process of claim 2 wherein the active compound is 1 lower alkyl 3,3 diphenyl 2 pyrrolidinone-4-propionyl chloride.

11. The process of claim 2 wherein the active compound is lower alkyl 1 lower alkyl 3,3 diphenyl- 2pyrrolidinone-4-propionate.

12. The process of claim 2 wherein the active compound is l-lower-alkyl-3,3-diphenyl-4-[fi-lower-alkyleneiminocarbonylethyl] -2.-pyrrolidinone.

13. The process of claim 2 wherein the active compound is l-isopropyl-3,3-dipheny1-4-[fi-pyrrolidinocarbonylethyl] -2-pyrrolidinone.

14. The process of claim 2 wherein the active compound is 4 ('y cyanoisopropyl) 3,3 diphenyl 1- lower-alkyl-2-pyrrolidinone.

15. The process of claim 2 wherein the active compound is 4-(B-morpholinocarbonylethyl) 3,3-diphenyl l-isopropyl-Z-pyr-rol-idinone.

16. The process of claim 2 wherein the active compounds is 4-(B-cyanoet-hyl)-3,3-diphenyl-l-lower-alkylQ- pyrrolidinonethion.

17. The process of claim 2 wherein the active compound is 1-loWer-alkyl-3,3-diphenyl-2-pyrrolidinonethion- 4-(N,Ndi-lower-a'1kylpropionamide) 18. The process of claim 2 wherein the active compound is 1-lower-alkyl-3, 3-diphenyl-2-pyrrolidinonethion- 4-propionyl chloride.

19. The process of claim 2 wherein the active compound is l-ower-alkyl 3,3-diphenyl-1-lower-allkyl 2-pyrrolidinonethion-4apropionate.

20. A pharmaceutical composition, useful for its analeptic effect, comprising (a) an effective amount of about one to milligrams of a compound of the formula:

E RII wherein Z is selected from the group consisting of cyano, carb-lower-alkoxy, carbonyl halide, lower-alkanoyl, and aminocarbonyl wherein amino is selected from the group consisting of primary amino, N-(lower-.alkyl)amino, N,N-di (lower-alkyDamino, N,N-di-(monocyc-lic alkyl)amino wherein each monocyclic alkyl has up to a maximum of nine carbon atoms, and saturated heterocyclic amino radicals having less than 12 carbon atoms and having up to a maximum of two hetero atoms in the heterocyclic Ting,

A is selected from the group consisting of loweralkyl, cycloalkyl having up to a maximum of nine carbon atoms, monocarbo-cyclic aryl, and monocarbocyclic aralkyl,

R is selected from the group consisting o f lower-alkyl, loWer-alkenyl, cycloalkyl having up to a maximum of nine carbon atoms, monocarbocyclic aryl, monocarbocyclic aralkyl, pyridyl, thienyl, and thenyl,

R is selected from the group consisting of lower-alkyl, lower-alkenyl, cycloalkyl having up to a maximum of nine carbon atoms, cycloalkenyl having up to a maxim-um of nine carbon atoms, and monocarbocyclic aralkyl,

R" is selected from the group consisting of hydrogen and methyl, a maximum of one R being other than hydrogen,

wherein E is selected from the group consisting of oxygen and sulfur,

wherein monocarbocyclic aryl and monocarbocyclic aralkyl has at most fifteen carbon atoms and 'has a radical which is selected from the group consisting of phenyl, nitrophenyl, lower-alk-oxyphenyl, lower-alkylmercaptophenyl, lower-alkylphenyl, and halophenyl, and wherein alkyl in aralkyl is lower-alkyl, and wherein n is selected from zero and one, and (b) a pharmaceutically acceptable carrier therefor.

21. A composition according to claim 20, wherein the active ingredient is 4 (/8-cyanoethyl)-3, 3 diphenyl-1- 1ower-alkyl-2-pyrrolidinone.

22. A composition according to claim 20, wherein the active ingredient is 4-(fl-cyanoethyl)-3,3-diphenyl-l-iso propyI-Zspyrrolidinone.

23. A composition according to claim 20, wherein the active ingredient is 4-( -cyanopropy1) 3,3-diphenyl-1- lower-alkyl-Z-pyrrolidinone.

24. A composition according to claim 20, wherein the active ingredient is l-lower-alkyl 3,3-diphenyl-2-pyrrolidinone-4-propionamide.

25. A composition according to claim 20, wherein the active ingredient is l-lower-alkyl 3,3-diphenyl-2-pyrrolidinone-4-(N-lowenalkylpropionamide) 26. A composition according to claim 20, wherein the active ingredient is l-lower-alkyl 3,3-diphenyl-2-pyrrolidinone-4-(N,N-di-lower-alkylpropionamide) 27. A composition according to claim 20, wherein the active ingredient is 1-'loweralkyl-3, 3-diphenyl-4-(fl-loweralkanoylethyl) 2-p-yvrr olidin one.

28. A composition according to claim 20, wherein the active ingredient is 1-lower-alkyl-3,3-diphenyl-2-pyrrolidinone-4-propiony1 chloride.

29. A composition according to claim 20, wherein the active ingredient is lower-alkyl 1-lower-alkyl3,3-diphenyl- 2-pyrrolidinone-4-propi0nate.

30. A composition according to claim 20, wherein the active ingredient is 1-lower-alkyl-3,3-diphenyl-4-[pi-loweralkyleneiminocarbonyl-et'hyl1 -2-.pyrro'lidinone.

31. A composition according to claim 20, wherein the active ingredient is 1-isopropyl-3,-3-diphenyl-4-[flpyrrolidinocarb onylethyl] -2-pyrro*lidinone.

32. A composition according to claim 20, wherein the 12 active ingredient is 4-( -cyanoisopropyl) 3,3 diphenyl- 1-lower-alkyl-Z-pyrrolidinone.

33. A composition according to claim 20, wherein the active ingredient is 4-(fi-morpholinocarbonylet-hyl)-3,3- diphenyl-l-isopropyl-Z-pyrro1idinone.

34. A composition according to claim 20, wherein the active ingredient is 4-(B-cy-anoethy1) -3,3-diphenyl-1-loweralkyl-2-py-rrolidinonethion.

35. A composition according to claim 20, wherein the active ingredient is 1-1ower-alkyl-3,3-diphenyl-2-pyrroli dinonet-hion-4- N,N-di-loWer-alkylpropionamide) 36. A composition according to claim 20, wherein the active ingredient is 1-lower-alkyl-3,*3-diphenyl-2-pyrrolidinonet hion-4 propionyl chloride.

37. A composition according to claim 20, wherein the active ingredient is lower-alkyl 3,3-diphenyl-l-lower-alkyl- 2apyrrolidinonet hion-4-pvropionate.

No references cited.

JULIAN S. LEVITT, Primary Examiner.

S. I. FRIEDMAN, Assistant Examiner. 

1. A PROCESS WHICH COMPRISES ADMINISTERING TO A LIVING ANIMAL BODY, FOR ITS ANALIPTIC EFFECT, AN EFFECTIVE AMOUNT OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 4-(OMEGA-SUBSTITUTED ALKYL)-2-PYRROLIDINONES AND -2THIONPYRROLIDINONES OF THE FORMULA: 